The HIV-1 pandemic continues at alarming rates and there is a clear need for novel preventative strategies. Results of four studies of antiretroviral agents (ARVs) given as pre-exposure prophylaxis (PrEP) have been recently reported and demonstrated effectiveness in reducing HIV transmission rates. However, in two studies, iPrEx and CAPRISA 004, in which adherence data have been presented in detail, there were dramatic differences in responses between participants with high levels of adherence versus those considered low adherers. Furthermore, another trial, FEM-PrEP, a multisite African study of daily oral FDC TDF/FTC versus placebo was stopped due to futility. Reasons for failure remain to be defined but issues surrounding adherence to protocol procedures have been suggested by the high pregnancy rates of participants in the active arm. Taken together, these trials have established the potential for ARVs to effectively prevent HIV-1 acquisition. However, with adherence being a main determinant of outcome, there is interest in alternatives to once daily oral therapy or coital-related applications of a microbicide gel. Eight properties have been identified as desirable for a next generation PrEP candidate. These include 1) a product that is safe for episodic and chronic use; 2) one that penetrates target tissue; 3) an antiviral that is protective against HIV-1 transmission at the site it penetrates; 4) a product that is long lasting; 5) one that displays a unique and high barrier to resistance; 6) an agent that lacks significant drug-drug interactions; 7) an antiviral that is not included in most current treatment regimens; and 8) a small molecule that is affordable to use and implement. We believe that GSK1265744- LONG ACTING (744-LA), a novel, strand transfer inhibitor of HIV-1, SIV, and SHIV integrase, has the potential to fulfill these criteria. This application outlines a basic and preclinical framework required to develop 744-LA as an effective and potentially revolutionary PrEP agent. This is based on the observation that a single 400 mg dose of 744-LA administered intramuscularly to six human volunteers resulted in plasma drug levels that remained in excess of the protein-adjusted IC90 for at least 42 days post administration in all treated subjects. Systemic pharmacokinetics in cynomologous monkeys dosed at 5 mg/kg demonstrated a comparable profile to that seen in humans. And importantly, the oral formulation of 744 has demonstrated robust antiviral activity dosed as once daily monotherapy in HIV-1 infected individuals. Accordingly, we propose to demonstrate that 744 has robust antiviral activity against a panel of transmitted isolates that are representative of the global pandemic. We will define the pharmacokinetic profile of the 5 mg/kg dose in rhesus macaques both systemically and in rectal and cervical secretions and tissue. Finally we will use the low dose intrarectal and the high dose intravaginal challenge models using R5 SHIVSF162P3 in rhesus macaques to demonstrate that 744-LA effectively prevents transmission and merits clinical development as a novel PrEP agent.